Saxagliptin suppresses degradation of type II collagen and aggrecan in primary human chondrocytes: a therapeutic implication in osteoarthritis.

Publisher: Taylor & Francis Country of Publication: England NLM ID: 101594777 Publication Model: Print Cited Medium: Internet ISSN: 2169-141X (Electronic) Linking ISSN: 21691401 NLM ISO Abbreviation: Artif Cells Nanomed Biotechnol Subsets: MEDLINE

Publication: 2015- : Abingdon, Oxford : Taylor & Francis
Original Publication: London : Informa Healthcare, [2013]-

Adamantane/*analogs & derivatives ; Aggrecans/*metabolism ; Chondrocytes/*drug effects ; Chondrocytes/*metabolism ; Collagen Type II/*metabolism ; Dipeptides/*pharmacology ; Osteoarthritis/*drug therapy ; Proteolysis/*drug effects; ADAMTS4 Protein/metabolism ; ADAMTS5 Protein/metabolism ; Adamantane/pharmacology ; Adamantane/therapeutic use ; Chondrocytes/pathology ; Dipeptides/therapeutic use ; Disease Progression ; Enzyme Activation/drug effects ; Gene Expression Regulation, Enzymologic/drug effects ; Glycation End Products, Advanced/pharmacology ; Humans ; Matrix Metalloproteinases/metabolism ; NF-KappaB Inhibitor alpha/metabolism ; NF-kappa B/metabolism ; Osteoarthritis/metabolism ; Osteoarthritis/pathology ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism

Osteoarthritis (OA) is a major public health concern for which a reliable non-invasive treatment option has yet to be developed. In the present study, we investigated the effects of saxagliptin, a novel dipeptidyl peptidase IV (DPP-4) inhibitor, on several important aspects of the pathophysiology of OA using primary human chondrocytes. The results of real-time PCR and ELISA analyses show that saxagliptin treatment significantly decreased mRNA and protein expression of three key cartilage degrading enzymes: matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13. The results of western blot confirmed that this decrease in MMP-1, -3, and -13 expression prevented degradation of type II collagen. We also found that saxagliptin significantly inhibited expression of a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-4 and ADAMTS-5, which was reflected by markedly decreased degradation of aggrecan. Inhibition of DPP-4 by saxagliptin also reduced oxidative stress in human primary chondrocytes as evidenced by decreased production of reactive oxygen species (ROS) and increased glutathione (GSH) levels. Additionally, the results of western blot analysis show that the effects of saxagliptin are mediated through the p38/IκBα/NF-κB pathway, which is considered an important treatment target for OA. These findings suggest a potential role for saxagliptin as a novel treatment against OA.

Keywords: ADAMTS; Saxagliptin; aggrecan; metalloproteinases (MMP); osteoarthritis (OA); p38/IκBα/NF-κB; type II collagen

0 (Aggrecans)
0 (Collagen Type II)
0 (Dipeptides)
0 (Glycation End Products, Advanced)
0 (NF-kappa B)
0 (Reactive Oxygen Species)
139874-52-5 (NF-KappaB Inhibitor alpha)
9GB927LAJW (saxagliptin)
EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
EC 3.4.24.- (ADAMTS5 Protein)
EC 3.4.24.- (Matrix Metalloproteinases)
EC 3.4.24.82 (ADAMTS4 Protein)
PJY633525U (Adamantane)

Date Created: 20190801 Date Completed: 20191230 Latest Revision: 20191230

20250114

10.1080/21691401.2019.1647223

31364869